Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells
- Munjal M. Acharyaa,
- Lori-Ann Christieb,
- Mary L. Lana,
- Peter J. Donovanc,
- Carl W. Cotmanb,
- John R. Fiked and
- Charles L. Limolia,1
- aDepartment of Radiation Oncology, University of California, Irvine, CA 92697-2695;
- bInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697-4540;
- cDepartments of Biological Chemistry and of Developmental and Cell Biology, and the Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697-3940; and
- dDepartment of Neurological Surgery, University of California, San Francisco, CA 94110
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Edited by James E. Cleaver, Room N431, University of California, San Francisco, CA, and approved September 30, 2009 (received for review August 17, 2009)
Abstract
Cranial irradiation remains a frontline treatment for the control of tumor growth, and individuals surviving such treatments often manifest various degrees of cognitive dysfunction. Radiation-induced depletion of stem/precursor cell pools in the brain, particularly those residing in the neurogenic region of the hippocampus, is believed, in part, to be responsible for these often-unavoidable cognitive deficits. To explore the possibility of ameliorating radiation-induced cognitive impairment, athymic nude rats subjected to head only irradiation (10 Gy) were transplanted 2 days afterward with human embryonic stem cells (hESC) into the hippocampal formation and analyzed for stem cell survival, differentiation, and cognitive function. Animals receiving hESC transplantation exhibited superior performance on a hippocampal-dependent cognitive task 4 months postirradiation, compared to their irradiated surgical counterparts that did not receive hESCs. Significant stem cell survival was found at 1 and 4 months postirradiation, and transplanted cells showed robust migration to the subgranular zone throughout the dentate gyrus, exhibiting signs of neuron morphology within this neurogenic niche. These results demonstrate the capability to ameliorate radiation-induced normal tissue injury using hESCs, and suggest that such strategies may provide useful interventions for reducing the adverse effects of irradiation on cognition.
Footnotes
- 1To whom correspondence should be addressed. E-mail: climoli{at}uci.edu
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Author contributions: C.L.L. designed research; M.M.A. and M.L.L. performed research; P.J.D. contributed new reagents/analytic tools; M.M.A., L.-A.C., C.W.C., and C.L.L. analyzed data; and M.M.A., L.-A.C., J.R.F., and C.L.L. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0909293106/DCSupplemental.
